Recombinaison homologue

Résumé

thumb | 275px | alt=Schéma du chromosome 1 après recombinaison homologue | Figure 1. La recombinaison homologue peut produire de nouvelles combinaisons d'allèles entre les chromosomes parentaux, notamment lors de la méiose.La recombinaison homologue est un type de recombinaison génétique où les séquences de nucléotides sont échangées entre des molécules d'ADN identiques (homologues) ou similaires (Figure 1). Au sens large, la recombinaison homologue est un mécanisme ubiquitaire de réparation des cassures double-brins de l'ADN. Sa caractéristique principale est l'utilisation d'une molécule d'ADN homologue intacte (comme la chromatide sœur) comme modèle pour la restauration de la séquence nucléotidique de la molécule lésée. Le transfert d'information génétique de la molécule intacte donneuse à la molécule lésée receveuse peut conduire à un évènement de conversion génique si les deux ADN recombinants ne sont pas de séquence identique. La résolution des intermédiaires tardifs de cette voi

Source officielle

https://fr.wikipedia.org/wiki/Recombinaison_homologue

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Difficulties to replicate telomeres - the ends of our chromosomes - can cause telomere shortening andgenome instability. These difficulties are due to the repetitive DNA sequence and distinct structures at telomeresthat challenge the semi-conservative DNA replication machinery. Among the proteins that help toovercome the obstacles to telomere replication are factors known to be mutated in genetic diseases (forinstance WRN, BLM, RTEL1, CTC1), but we suspect that there are still factors and pathways unknown.DNA replication defects at telomeres manifest as smeary or multiple telomeric fluorescence in situ hybridization(FISH) signals on metaphase chromosomes - commonly called telomere fragility. To identify proteinsthat protect human telomeres from fragility, we depleted 71 proteins (including 8 controls) from HeLa cellsusing siRNA pools and analysed their metaphase chromosomes for fragile telomeres. The majority of theseproteins had been identified by QTIP-iPOND - a proteomic analysis of chromatin near telomere replicationforks. Among the 71 proteins that were depleted in the siRNA screen, we identified 29 novel proteins thatprevent telomere fragility and are therefore crucial to maintain genome stability. The telomere fragilityscreen validated QTIP-iPOND as a technique to identify telomere replication proteins. The hits identified inour telomere fragility screen may for example have functions in regulating telomeric chromatin compositionand compaction, regulating transcription of the telomeric long non-coding RNA TERRA and its associationwith telomeric chromatin, dealing with replication stress and stalled replication forks, modulating DNAdamage signalling and repair, modulating sister chromatid cohesion, and preventing oxidative stress.One of the 29 novel proteins identified in the telomere fragility screen is chromobox 8 (CBX8) whose functionat telomeres was investigated in further detail in this study. CBX8 is a component of the canonical polycombrepressive complex 1 (PRC1), an epigenetic regulator of gene expression. However, CBX8 also hasfunctions that are independent of the PRC1 complex. We show that human CBX8 prevents telomere fragilitycaused by RNA-DNA hybrids which could stall replication forks and induce homologous recombination.CBX8 depletion or knockout did however not affect telomeric RNA-DNA hybrid levels. We hypothesize thatCBX8 may be involved in repair activities at stalled replication forks that arise when the replisome encounterspersistent RNA-DNA hybrids. Moreover, we found that CBX8 localizes to telomeric repeat-binding factor2 (TRF2)-deficient telomeres in a manner that is dependent on RNA-DNA hybrids and ATM signalling.We demonstrate that H3K27me3 (trimethylated histone 3 lysine 27) marks, which have previously beensuggested to help recruitment of CBX proteins to chromatin via the CBX chromodomain, are dispensable forCBX8 recruitment to TRF2-deficient telomeres. Furthermore, we found that CBX8 promotes non-homologousend joining (NHEJ)-mediated telomere fusions of dysfunctional telomeres. We therefore hypothesizethat CBX8 is involved in repair activities that influence the DNA repair pathway choice at TRF2-deficient telomeres.

EPFL2022

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Genetic manipulation of Vibrio cholerae by combining natural transformation with FLP recombination

Melanie Blokesch, Olga de Souza Silva

Even though Vibrio cholerae is a well-known human pathogen, it is also a normal member of aquatic habitats. Within this environment it often forms biofilms on the chitin-containing exoskeleton of crustaceans and their molts. Chitin not only serves as nutrient source but also induces a developmental program called natural competence. Naturally competent bacteria take up free DNA and integrate it into their genome by homologous recombination, thereby becoming naturally transformed. In this study, we made use of the knowledge on the environmental lifestyle of V. cholerae to genetically manipulate its genome. We achieved this by combining the methods of chitin-induced natural transformation and Flp recombination. Using this approach, we disrupted several genes by insertion of FRT-site-flanked antibiotic-resistance cassettes. The cassettes were subsequently excised by induction of the Flp recombinase, which acts on the FRT sites. This method represents a simplified and faster alternative to standard gene deletion techniques, which often depend on bacterial conjugation and the availability of suicide vectors.

Elsevier2010

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TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection

Eric Aeby, Jing Ye

The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps similar to 90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting telomeres against non-homologous end joining (NHEJ). In Top-less cells, the protection against NHEJ is alleviated if the expression of the TRF2-interacting protein RAP1 is reduced. We conclude that a distinctive topological state of telomeric DNA, controlled by the TRF2-dependent DNA wrapping and linked to t-loop formation, inhibits both ATM activation and NHEJ. The presence of RAP1 at telomeres appears as a backup mechanism to prevent NHEJ when topology-mediated telomere protection is impaired.

Cell Press2016

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EPFL2022